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Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.

Clif BarryNational Institute of Allergy and Infectious DiseasesBethesda, Maryland, United States

Grand Challenges China

China - New Interventions

14 Nov 2016

Clif Barry of The National Institute of Allergy and Infectious Diseases in the U.S., working with Qian Gao of Shanghai Medical College Fudan University in China, will support a clinical trial to shorten the treatment time for tuberculosis (TB) from six months to four months by helping to identify predictive biomarkers in individuals that only require the shorter treatment. Shortening treatment when possible will substantially reduce costs and the emergence of drug resistance, which is a major barrier to eradicating this deadly disease. The phase 2b clinical trial will recruit 620 TB patients at multiple clinics in South Africa and China who will be monitored for disease burden by PET/CT scans and diagnostic assays during treatment, and will supply blood and sputum samples for testing. He will analyze RNA and inflammatory markers in serum samples from the Chinese trial participants to identify more robust biomarkers for predicting shorter treatments. He will also determine the strains of the causative Mycobacterium tuberculosis, the source of any reinfection (relapse or new infection), and the presence of drug resistant bacteria in these patients, and how these link with treatment duration and disease outcome.

Qian Gao of Shanghai Medical College Fudan University in China, working with Clif Barry of The National Institute of Allergy and Infectious Diseases in the U.S., will support a clinical trial to shorten the treatment time for tuberculosis (TB) from six months to four months by helping to identify predictive biomarkers in individuals that only require the shorter treatment. Shortening treatment when possible will substantially reduce costs and the emergence of drug resistance which is a major barrier to eradicating this deadly disease. The phase 2b clinical trial will recruit 620 TB patients at multiple clinics in South Africa and China who will be monitored for disease burden by PET/CT scans and diagnostic assays during treatment and will supply blood and sputum samples for testing. He will analyze RNA and inflammatory markers in serum samples from the Chinese trial participants to identify more robust biomarkers for predicting shorter treatments. He will also determine the strains of the causative Mycobacterium tuberculosis the source of any reinfection (relapse or new infection) and the presence of drug resistant bacteria in these patients and how these link with treatment duration and disease outcome.

Ling Ye of Emory University in the U.S., working with Lu Lu of Shanghai Medical College, Fudan University in China, will design a potent HIV vaccine using selected sequences of one of the virus's envelope proteins to trigger the production of broadly neutralizing antibodies. This has been problematic due to the diversity of the viral envelope glycoprotein and its glycosylation shield which prevent the immune system from recognizing it. The membrane-proximal external region (MPER) of the viral envelope protein has been identified as an attractive target for inducing neutralizing antibodies and they have fused it with another viral protein to form a chimera that can partly neutralize infection. They will build on this result by modifying the structure of the MPER to stabilize it in a more active conformation and by fusing it with slightly different viral proteins that can then be immunized altogether. They will evaluate whether this vaccine strategy further stimulates broadly neutralizing antibody production and can fully neutralize HIV in several animal models.

Lu Lu of Shanghai Medical College, Fudan University in China working with Ling Ye of Emory University in the U.S., will design a potent HIV vaccine using selected sequences of one of the virus's envelope proteins to trigger the production of broadly neutralizing antibodies. This has been problematic due to the diversity of the viral envelope glycoprotein and its glycosylation shield, which prevent the immune system from recognizing it. The membrane-proximal external region (MPER) of the viral envelope protein has been identified as an attractive target for inducing neutralizing antibodies, and they have fused it with another viral protein to form a chimera that can partly neutralize infection. They will build on this result by modifying the structure of the MPER to stabilize it in a more active conformation, and by fusing it with slightly different viral proteins that can then be immunized altogether. They will evaluate whether this vaccine strategy further stimulates broadly neutralizing antibody production and can fully neutralize HIV in several animal models.

Paul MacAry of the National University of Singapore in Singapore, working with Babak Javid of Tsinghua University in China, will study human monoclonal antibodies that protect individuals from infection by Mycobacterium tuberculosis and could be used to develop a tuberculosis vaccine. Tuberculosis is the world's most deadly infectious disease and the causative bacteria are present in latent form in up to a quarter of the global population. They have discovered protective antibodies in three health care workers who are exposed to very high levels of Mycobacterium tuberculosis. They will isolate these antibodies from memory B cells to study how they bind to the bacteria and trigger a protective immune response. They will then develop an assay to screen larger numbers of workers to isolate and characterize more potent human antibodies that could be used to design an effective vaccine.

Babak Javid of Tsinghua University in China, working with Paul MacAry of the National University of Singapore in Singapore, will study human monoclonal antibodies that protect individuals from infection by Mycobacterium tuberculosis and could be used to develop a tuberculosis vaccine. Tuberculosis is the world's most deadly infectious disease, and the causative bacteria are present in latent form in up to a quarter of the global population. They have discovered protective antibodies in three health care workers who are exposed to very high levels of Mycobacterium tuberculosis. They will isolate these antibodies from memory B cells to study how they bind to the bacteria and trigger a protective immune response. They will then develop an assay to screen larger numbers of workers to isolate and characterize more potent human antibodies that could be used to design an effective vaccine.

Tongqing ZhouNational Institutes of HealthBethesda, Maryland, United States

Grand Challenges China

China - New Interventions

11 Apr 2017

Tongqing Zhou of the Foundation for the National Institutes of Health Inc. in the U.S., working with Linqi Zhang of Tsinghua University in China, will design a broadly protective vaccine against HIV-1 derived from the atomic structure of the viral envelope protein from the dominant transmitted founder HIV-1 strain isolated from a high-risk population in China. HIV is a rapidly evolving virus that continually alters its structure to elude the immune system and antiretroviral drugs. This makes it challenging to develop an effective vaccine. The spike-shaped envelope protein complex of HIV extends from its surface to fuse with and infect human cells. Prior to cell fusion this complex is folded into a closed conformation and is protected from immune cells by glycan molecules. They will use the known sequence and structure of the viral envelope protein to design and synthesize stabilized pre-fusion conformations that display accessible antibody binding sites that may make them more effective vaccines. The immunogenicity of these vaccines will be tested in small animal models and non-human primates.

Linqi Zhang of Tsinghua University in China, working with Tongqing Zhou of the Foundation for the National Institutes of Health Inc. in the U.S., will design a broadly protective vaccine against HIV-1 derived from the atomic structure of the viral envelope protein from the dominant transmitted founder HIV-1 strain isolated from a high-risk population in China. HIV is a rapidly evolving virus that continually alters its structure to elude the immune system and antiretroviral drugs. This makes it challenging to develop an effective vaccine. The spike-shaped envelope protein complex of HIV extends from its surface to fuse with and infect human cells. Prior to cell fusion, this complex is folded into a closed conformation and is protected from immune cells by glycan molecules. They will use the known sequence and structure of the viral envelope protein to design and synthesize stabilized pre-fusion conformations that display accessible antibody binding sites that may make them more effective vaccines. The immunogenicity of these vaccines will be tested in small animal models and non-human primates.

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